Vantage Snippets are short summaries of breaking news stories.
Despite Bavencio winning US approval in combination with Inlyta in first-line renal cell cancer today – a month earlier than expected – Pfizer and Merck KGaA’s anti-PD-L1 antibody appears to be more of an also-ran. Both Bristol-Myers Squibb’s Opdivo (in combination with Yervoy) and Merck & Co’s Keytruda (in combination with Inlyta) are already approved in this setting and each can claim to have an edge over Bavencio. Opdivo’s advantage is being first to market, having been approved in April 2018; Keytruda’s is trial data that appear to be superior – Bavencio looks worse on all of the key outcomes detailed below, and the disparity in the hazard ratios is particularly damning (Asco-GU 2019 – Checkpoint blockers might not be created equal after all, February 20, 2019). Bavencio did demonstrate superiority over Sutent, still the standard of care for now at least, boosting median PFS by more than five months over the older drug. Analysts from Bernstein state that renal cancer will be Bavencio’s main revenue driver, but that they expect Keytruda/Opdivo to “win” overall. They see peak Bavencio sales of $600m, $280m of which will go to Merck KGaA under a profit-share agreement.
|Cross-trial comparison in first-line renal cancer|
|Drug||Study||ORR||CR||PFS||HR for OS|
|Bavencio + Inlyta||Javelin Renal 101||52%||3%||13.8mth||0.78*|
|Keytruda + Inlyta||Keynote-426||59%||6%||15.1mth||0.53|
|Opdivo + Yervoy (int/poor)||Checkmate-214||42%||11%||11.6mth||0.66|
|Source: Asco-GU, Dr Lori Wood. Note: *data premature.|
Endorsement by an FDA advisory committee for one of the two oncology drugs that Daiichi Sankyo had up for review gives the Japanese pharma’s cancer ambitions a small boost. The panel voted in favour of pexidartinib for a rare tumour of the tendon sheaths, but against quizartinib for an aggressive form of acute myeloid leukaemia. Neither agent is seen as having substantial prospects – sales forecasts for quizartinib are certainly heading south – but there is much more to come from Daiichi in oncology. The company recently signalled a boost to investment into its pipeline of antibody-drug conjugates; the lead asset here is the Astrazeneca-partnered DS-8201, a Her2-targeted project that could be filed for US approval later this year (Astra and Daiichi lay out their plan for a better Herceptin, May 8, 2019). Earlier-stage ADCs from Daiichi will be on show at Asco next month: phase I lung cancer data on both US-1402, an anti-Her3 agent, and DS-1062, which hits Trop2, are slated for presentation. Investor meetings being held alongside the cancer conference will be scrutinised for any insight into a new business plan, which executives have also promised to deliver. Yesterday’s FDA panel looks to mark the beginning of a busy period for Daiichi Sankyo’s oncology division.
|Daiichi Sankyo's oncology efforts|
|Annual Sales WW ($m)|
|Quizartinib||FLT 3 inhibitor||Ambit Biosciences||84||185||263|
|Pexidartinib||CSF-1R, c-kit & FLT 3 inhibitor||Plexxikon||51||114||169|
|DS-8201 (trastuzumab deruxtecan)||Anti-Her2 ADC||Astrazeneca 50/50 profit share||100||741||1,790|
|U3-1402||Anti-Her3 ADC||Daiichi Sankyo||-||35||75|
|DS-1062||Anti-Trop 2 ADC||Daiichi Sankyo||-||-||-|
|DS-1647||HSV 1 oncolytic virus||Daiichi Sankyo||-||-||-|
|PLX2853||BRD 4 inhibitor||Plexxikon|
|DS-3032 (milademetan)||MDM 2 inhibitor||Rigel Pharmaceuticals|
|DS-3201 (valemetostat)||EZH 1 & 2 inhibitor||Daiichi Sankyo||-||-||-|
|DS-1001||IDH 1 inhibitor||Daiichi Sankyo||-||-||-|
|DS-1205||AXL inhibitor||Daiichi Sankyo||-|
|Note: Not all products have attracted sellside sales forecasts. Source: EvaluatePharma.|
Already in dire trouble when its stock fell 70% on a woeful efficacy showing by its Duchenne muscular dystrophy gene therapy SGT-001 in February, Solid Bioscience has suffered again. The group has lost more than a third of its remaining value so far today after a patient in the same trial, Ignite-DMD, experienced worrying toxicity. Solid had continued with the trial despite the poor expression of the microdystrophin transgene in the first three patients, and had ramped up the dose; this appears to have backfired badly. The only patient to take the higher 2x1014 vg/kg dose of SGT-001 experienced a gastrointestinal infection unrelated to the drug and a transient decline in platelet count that was drug-related but non-serious. However, the elevation of transaminases and increase in bilirubin higher than twice the upper limit of normal, indicating potential liver injury, had to be reported to the FDA as a drug-related serious adverse event. Despite this latest setback Solid is ploughing on and Ignite-DMD patient enrolments are set to continue. Preliminary data are due in the second half of this year; alongside safety, investor focus will return to efficacy – this should give a clearer idea if Solid, which only has enough cash to get it to early 2020, has a real future in this space.
It does not take much digging to find reasons for Minerva Neurosciences’ 14% share price drop today, in the wake of a press release heralding “positive” results for its depression project, seltorexant. The lack of dose response immediately raises a red flag, as does the mention of only one secondary endpoint – 19 are specified in the trial design. Throw in a controversial use of statistics, and it is no wonder that investors are unconvinced. The study, in 287 patients with major depressive disorder, tested three doses of seltorexant. A 40mg dose cohort was stopped at an interim analysis, while a 10mg cohort was “not interpretable” due to the small sample size. Bang in the middle is the sweet spot, according to Minerva: the 20mg group showed a statistically significant improvement on the MADRS depression scale compared with placebo, with a p value of 0.083. This would normally be considered a fail, of course, but Minerva employed a two-sided p-value test, with a pre-specified type 1 error level of 0.1. Shareholders will be hoping for a much more convincing win in the coming weeks, when a crucial pivotal trial of the company’s lead asset, roluperidone in schizophrenia, is due to read out.
|Minerva's late-stage pipeline|
|Product||Mechanism of Action||Trial details|
|Roluperidone (MIN-101)||5-HT2A receptor antagonist; Sigma-2 opioid receptor agonist||Phase III schizophrenia trial ongoing (NCT03397134)|
|Seltorexant (MIN-202)||Orexin 2 receptor antagonist||Three phase IIb trials ongoing. MDD dose finding (NCT03227224); insomnia (NCT03375203); MDD vs Seroquel (NCT03321526).|
|MIN-117||5-HT1A & 5-HT2A receptor antagonist; Alpha-1 & Alpha-2 adrenoceptor agonist.||Phase II MDD trial ongoing (NCT03446846)|
|MDD = major depressive disorder. Source: EvaluatePharma.|
Caveat emptor. Executives at French group Pierre Fabre might be wishing they had brushed up on their Latin before shelling out $60m up front for European and African rights to Puma Biotechnology’s breast cancer drug Nerlynx. Fabre’s decision to buy in came less than six weeks before Puma reported disastrous first-quarter results, showing that Nerlynx had significantly missed expectations. First-quarter sales of $45.6m came up considerably short of the $67m the market had been expecting, prompting a slew of analyst downgrades and a 20% drop in Puma shares. The miss was largely down to patient discontinuations due to severe diarrhoea, a side-effect of Nerlynx that requires anti-diarrhoeal medication to be indicated as part of treatment. It seems that even these measures cannot persuade already sick patients to remain on the therapy – nor, more importantly, to lure new patients in to replace those who have made it through the 12-month treatment window. Alongside the $60m Pierre Fabre has already paid, the group is also on the hook for $345m in regulatory and commercial milestones. Given the worsening outlook for Nerlynx, Pierre Fabre might be grateful that it chose such a back-end heavy deal.
A year after pulling off the largest Swiss biotech IPO in over 10 years Polyphor has reminded its new investors about of the risks of drug development. Two phase III trials of its lead asset, an experimental antibiotic called murepavadin, have been halted on higher than expected rates of acute kidney injury. This was known to be a potential issue with the project but Polyphor believed that toxicities could be managed; a safety analysis is being conducted and a decision will be made in the coming months on whether the project is salvageable. The signs are not promising – Polyphor said 56% of patients treated met the criteria for acute kidney injury, much higher than expected. Murepavadin has been designed to fight the superbug Pseudomonas aeruginosa, a multidrug-resistant pathogen against which new agents are desperately needed, but even here this level of toxicity is unlikely to be acceptable. The company mooted fixes such as changing the trials’ inclusion criteria or dosing regimens, but investors appear to be expecting the worst: Polyphor shares fell a further 21% today after slumping 49% on Friday, valuing the company at SFr116m ($113m), below its year-end cash of SFr134m.
The Crispr company Verve Therapeutics was launched this week with a funding round of $58.5m led by Google’s venture arm, GV. And Verve is also partnering with Google’s sister company Verily, whose nanoparticle technology will be used to help develop drugs for coronary artery disease. This is a bit of a change of plan on Verily’s part – it had initially intended to use the nanoparticles, on which it has been working since it was still a part of Google X, for diagnostic applications. The notion then was that the particles would attach to particular types of cells and be detected by a separate device. But the group now says that, theoretically at least, nanoparticles can be engineered to deliver therapies to individual cells or tissues, though it admits that it will be tough to develop a product capable of targeting drug delivery that precisely. It is focusing on lipid-based nanoparticles including liposomes, which it hopes will fuse with the targeted cell’s membrane and deliver the therapeutic payload – Verve’s Crispr nucleases and base editors. Combining two still unproven concepts is risky; still, with a market cap of more than $800bn, Google will be able to cope if its investment goes south.
|Verve Therapeutics’ venture funding|
|Date||Round||Investment ($m)||Lead investor||Investor|
|May 7, 2019||Series A||58.5||Yes||GV|
|-||Arch Venture Partners|
|Source: Company communications.|
After months of sitting on the bench Pfizer is back in the M&A game with the buyout of the private Swiss biotech Therachon, for an initial $340m. The purchase price might be little league but the move is right in Pfizer’s rare disease wheelhouse, giving it TA-46, a phase I candidate for achondroplasia, also known as short-limbed dwarfism. Pfizer’s focus is primarily on TA-46 and the follow-on agent TA-100, so the rest of Therachon, which includes the short bowel syndrome project apraglutide, will be spun out into a new company. The pharma giant will retain a stake in this via its venture arm Pfizer Ventures, which participated in Therachon's $60m fund raising last year. In taking a punt on achondroplasia Pfizer will be competing against Biomarin’s vosoritide, the most advanced research project in this field. Biomarin is conducting a 110-patient trial in 5-14 year olds that is due to read out by the end of the year. But vosoritide has not been without its issues, and the injection of Pfizer’s cash and knowhow could narrow the gap between the two assets.
|Selected achondroplasia assets|
|Project||Company||Status||2024e sales ($m)|
|Vosoritide||Biomarin Pharmaceutical||Phase III||586|
|TransCon CNP||Ascendis Pharma||Phase I||21|
The $1bn Johnson & Johnson is reported to have paid to settle lawsuits around its defective Pinnacle range of hip implants is a hefty amount of money – but it is dwarfed by the $2.9bn in cash it paid in 2013 to settle claims from plaintiffs harmed by its ASR hips. Perhaps this is why shareholders barely reacted, sending the shares down just 1.5%. Yesterday’s settlement put about 95% of the 6,000 or so Pinnacle claims to bed, but the remainder will take more time and money. And J&J has other legal wrangles to think about. Most of the US cases of the company's pelvic mesh implant litigation have been resolved, but class actions have begun in several other countries. It is also on the hook for $4.7bn as a result of its baby powder being linked with ovarian cancer and mesothelioma. Billion-dollar fines might be viewed as a cost of doing business for these hugely profitable, multinational healthcare companies, but surely only up to a point. The bills are adding up for J&J, and while executives have expressed confidence in overturning the baby powder verdicts, losing could cause a more dramatic shareholder reaction.
Mallinckrodt’s efforts to expand beyond its best-seller, H.P. Acthar gel, have again come up against a brick wall. The company has abandoned CPP-1X plus sulindac after the combination failed a phase III trial in familial adenomatous polyposis. The project had been seen as the group’s most promising pipeline prospect, but that is not saying much: EvaluatePharma sellside consensus forecast sales of $49m in 2024. No matter, Mallinckrodt has other important readouts approaching, but a couple of these feature a familiar name: Acthar. First-quarter sales of the product disappointed, but Mallinckrodt still reckons it can hit $1bn this year, helped by upcoming data in rheumatoid arthritis and multiple sclerosis. Beyond Acthar, Mallinckrodt is looking to phase III projects including its skin substitute Stratagraft and terlipressin. And it has not given up on its Nieman-Pick C disease candidate VTS-270, despite a pivotal trial failure last year. During yesterday’s earnings call Mallinckrodt said it had conducted various post-hoc analyses and would meet the FDA to discuss the project’s next steps. With the DOJ still investigating alleged improper sales practices at Acthar’s originator, Questcor, Mallinckrodt could do with something more promising to turn to.
|Key Mallinckrodt readouts in 2019|
|Project||Indication||Trial||Data due||2024e sales ($m)|
|H.P. Acthar Gel||Rheumatoid arthritis||Phase IV, NCT02919761||Jun 2019||273*|
|Multiple sclerosis||Phase IV, NCT03126760||H2 2019||229*|
|Stratagraft||Partial thickness burns||Phase III, NCT03005106||Late 2019||32|
|Xenex||Neuroprotection post-cardiac arrest||Phase III, NCT03176186||H2 2019||26|
|Terlipressin||Hepato-renal syndrome||Phase III, NCT02770716||Late 2019||–|
|*Indication sales. Source: EvaluatePharma.|